REVIEWED BY:

Teim Jengoa Eyo. MBBS, MRCPCH
ST5 Paediatrics Trainee
Neonatal Intensive Care Unit, Heartlands Hospital
Bordesley Green East, Birmingham, B9 5SS, United Kingdom
Corresponding author email: teim.eyo1@nhs.net

Diana Aguirre. BMedSci, BMBS, MRCPCH, PGCert (multidisciplinary simulation)
ST7 Neonatal GRID trainee
Neonatal Intensive Care Unit, Heartlands Hospital
Bordesley Green East, Birmingham, B9 5SS, United Kingdom

Harsha Gowda. MBBS, MSc, FRCPCH
Neonatal Consultant
Neonatal Intensive Care Unit, Heartlands Hospital
Bordesley Green East, Birmingham, B9 5SS, United Kingdom

MANUSCRIPT CITATION:

Hodgson KA, Owen LS, Kamlin COF, Roberts CT, Newman SE, Francis KL, Donath SM, Davis PG, Manley BJ. Nasal High-Flow Therapy during Neonatal Endotracheal Intubation. N Engl J Med. 2022 Apr 28;386(17):1627-1637. doi: 10.1056/NEJMoa2116735. PMID: 35476651

TYPE OF INVESTIGATION: Prevention

FUNDING: None

CONFLICT OF INTEREST: None

QUESTION: (P) In neonates undergoing endotracheal intubation via the oral route (I)Does the use of high-flow oxygen (C) Compared to standard care that is no high flow or supplemental oxygen during the procedure (O)Increase the number of successful intubation without physiological instability (T) during the first intubation attempt in the delivery room or on the neonatal intensive care unit?

METHODS

Design: Randomised controlled, non-blinded, multicentre trial.

Allocation and Stratification: Eligible infants were randomised and stratified based on trial centre, gestation (less than or equal to 28 weeks or greater than 28 weeks), and the use of premedication (yes or no). For multiple siblings, intubation randomisation was on an individual basis. Fixed criteria were used to determine the inclusion of subsequent intubation episodes in the same infant as independent events to be analysed.

Blinding: Clinicians were not blinded to the intervention.

Follow-up period:  Follow-up data were available for 97.2% of patients through their hospitalization. Patients were followed up for 72hours post-randomisation for adverse events.

Setting: Two Australian-based level 3 neonatal units from November 2018 to April 2021.

Inclusion: Endotracheal intubation via the oral route in the delivery room or neonatal unit.

Exclusion criteria: Nasal intubation, urgent intubation determined by the treating clinician, pre-randomisation heart rate below 120 beats per minute, cyanotic congenital heart disease, suspected or proven Coronavirus (COVID-19) infection in the infant or mother, and contraindications of high-flow therapy like congenital diaphragmatic hernia, congenital nasal anomaly, or abdominal wall defect.

Patients: 258 intubations in 209 newborns were randomly allocated to either the high-flow group or standard care group (129 intubations each). After excluding 7 intubations, 251 were included in the primary intention to treat analysis.

Intervention: Neonates in the high-flow group had fitted binasal cannulae applied on the removal of existing ventilatory support before the application of the laryngoscope. Oxygen was increased to 100% if saturation dropped to less than 90% during laryngoscopy. High-flow therapy was continued throughout laryngoscopy and discontinued after the completion of intubation.

Control: In the standard-care group, intubation was undertaken without high-flow therapy or supplemental oxygen.

Primary outcome: Successful first attempt at intubation without physiological instability.

The study defined physiological instability as desaturation or bradycardia during the first intubation attempt.

Secondary outcomes: Median oxygen saturation during intubation attempt, time to and length of desaturation event (if applicable), duration and number of attempts at intubation.

Analysis and Sample Size: Previous data from the lead site showed a success rate of 29% for the first attempt at endotracheal intubation devoid of physiologic instability. To increase this value to 50%, with 90% power and a type 1 error of 0.05, an estimated value of 246 intubations (123 intubations in each treatment group) was determined.

On account of collinearity with other stratification factors, stratification based on trial-centre was not included in the analyses of the primary outcome as planned.

Statistical methods used included a comparison of means using linear regression for non-skewed data and a comparison of medians and quantile regression for skewed data. Risk differences and confidence intervals were also reported. Prespecified subgroup analyses of the primary outcomes were performed with the use of logistic regression models for subgroups.

Patients follow-up: 462 intubations were eligible for the study, 204 were excluded from randomisation (129 due to non-availability of researcher, 45 due to lack of prospective consent and 32 due to non-notification of a researcher). Intention to treat analysis was performed. A total of 258 intubations in 202 infants (129 intubations in each arm) were randomised.

 Seven endotracheal intubation episodes were excluded. 3 were due to non-occurrence of intubation, 2 due to randomisation error as exclusion criteria were met, 1 for indeterminate primary outcome and one, parents declined retrospective consent. Thus, 96% of patients in the high-flow group (124 of 129) and 98% in the control group (127 of 129) were included in the analysis. Patients were followed-up from randomisation to 72hours after for adverse effects.

MAIN RESULTS:

All enrolled infants were matched demographically and on clinical characteristics.

Primary Outcome:

Outcome	High flow    Total= 124	Standard care Total =127	Adjusted risk difference (95% CI)
Successful first attempt at intubation devoid of physiological instability	60 (50%)	40 (31.5%)	17.6 (6 to 29.2)
Successful intubation at first attempt	85 (68.5%)	69 (54.3%)	15.8 (4.3 to 27.3)
Absence of physiologic instability	79 (63.7%)	64 (50.4%)	13.4 (1.2 to 25.5)

Primary Outcome Based on Subgroup Stratification:

	Total number of high-flow group	Successful intubation on the first attempt	Total number in Standard Care Group	Successful intubation on the first attempt	Adjusted risk difference
Post Menstrual Age
</= 28 weeks	64	34 (53.1%)	66	23 (34.8%)	16.8 (0.3 to 33.2)
> 28 weeks	60	28(46.7%)	61	17(27.9%)	20.3 (5.8 to 35.7)
Premedication Use
Yes	92	50(54.3%)	93	30 (32.3%)	20.1(7.1 to 34.2)
No	32	12 (37.5%)	34	10(29.4%)	13.5(-7.2 to 34.1)
Operator Experience
Inexperienced (<20 past intubations)	61	30 (49.2%)	51	8(15.7%)	33.3 (18.3 to 48.2)
Experienced (>20 past intubations)	63	32(50.8%)	76	32(42.1%)	7.5(-9.4 to 24.3)

No clinically significant differences were noted in secondary outcomes in both groups.

The percentage of serious adverse events was similar in both groups.

Repeated events leading to intubations in individual infants were randomised using prespecified sensitivity analysis.  For twin births, post hoc sensitivity analysis was used to account for within-sibling correlations. Both of which yielded results like those of the primary outcome analysis.

CONCLUSION

The authors concluded that the trial showed clinically important improvement in terms of intubation success and the maintenance of physiological stability with high-flow therapy, with greater benefit demonstrated in inexperienced operators who take longer and are more likely to be unsuccessful. The overall number needed to be treated was 6 for 1 infant to benefit. The intervention was not associated with increased risk.

COMMENTARY:

Intubation remains essential for clinicians, especially when dealing with preterm and very sick neonates. Clinicians, however, are becoming less proficient due to intubations being de-emphasized secondary to factors like the growing use of non-invasive respiratory support (1) and the rising use of less invasive surfactant administration techniques in preterm infants(2).

A large multicentre study showed an average success of 49% on the first intubation attempt; this fell to 24% with inexperienced operators (3). The likelihood of physiological instability during intubation attempts is increased in neonates due to lower functional residual capacity (4,5) and higher metabolic demands (5), the most common cause for abandoning intubation (6).

Kids THRIVE, a multicentre randomised controlled trial, showed high flow therapy to aid successful elective intubations in infants and children via prolonging the safe, apnoeic oxygenation time (7). The proposed mechanism is that constant insufflation promotes oxygenation and carbon dioxide removal through gaseous mixing and flushing of the dead space(8).

This study aims to provide evidence of the role of high-flow therapy in improving success and reducing physiologic instability during neonatal intubations. This is the first appropriately powered, randomized study of this population addressing this clinical question. It is written up methodically, with rational and detailed methods and results. There are clear inclusion and exclusion criteria. Relevant subgroup analyses for the primary outcome were performed.

The success on the first attempt at intubation but sans physiological instability was achieved in 50% of the high-flow group and 31.5% of the standard care group; the number needed to treat for one infant to benefit was six. Successful first-attempt intubation, regardless of physiologic instability, was 68.5% vs. 54.3% in the high-flow and standard-care groups, respectively, which are comparable to previous studies (3).

In subgroup analysis, regardless of gestation (≤ or ˃28 weeks) and premedication use status (yes or no), the high-flow group had higher success rates at first intubation than the standard care group. Among inexperienced operators, a significantly higher success rate was seen in the high-flow group (49.2% vs. 15.7%).

There are some limitations to this study. It lacks long-term outcomes, posing the question of the longer-term benefit of a successful first attempt at intubation without physiological instability. However, repeated intubation attempts are known to have adverse effects (9). The study also lacks a cost analysis of using additional equipment (high-flow) during the procedure. If the infant is already on high flow before intubation, the same equipment can be used, eluding any additional cost. Furthermore, it is difficult to determine whether the benefit is due to high flow, supplemental oxygen through high flow and or placebo effect on the clinician performing the procedure, who might feel less pressured to intubate quickly with ongoing respiratory support.

In summary, the study showed that using high-flow during non-emergency neonatal endotracheal intubations increased success at the first attempt but sans physiological instability, with greater benefit seen in inexperienced operators. Clinicians may need to consider adopting this practice in their local units.  Future studies should focus on cost-effectiveness and long-term neurodevelopmental outcomes.                                                        

REFERENCES:

1. Carlo WA, Polin RA, Papile LA, Tan R, Kumar P, Benitz W, et al. Respiratory support in preterm infants at birth. Paediatrics. 2014 Jan;133(1):171–4.

2. Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: A systematic review and meta-analysis. Vol. 102, Archives of Disease in Childhood: Fetal and Neonatal Edition. 2017.

3. Foglia EE, Ades A, Sawyer T, Glass KM, Singh N, Jung P, et al. Neonatal intubation practice and outcomes: An international registry study. Paediatrics. 2019;143(1).

4. Gerhardt T, Reifenberg L, Hehre D, Feller R, Bancalari E. Functional residual capacity in normal neonates and children up to 5 years of age determined by an N2 washout method. Pediatr Res. 1986;20(7).

5. King W, Petrillo T, Pettignano R. Enteral nutrition and cardiovascular medications in the paediatric intensive care unit. Vol. 28, Journal of Parenteral and Enteral Nutrition. 2004.

6. Haubner LY, Barry JS, Johnston LC, Soghier L, Tatum PM, Kessler D, et al. Neonatal intubation performance: Room for improvement in tertiary neonatal intensive care units. Resuscitation. 2013;84(10).

7. Humphreys S, Lee-Archer P, Reyne G, Long D, Williams T, Schibler A. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) in children: A randomised controlled trial. Br J. Anaesth. 2017;118(2).

8. Patel A, Nouraei SAR. Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE): A physiological method of increasing apnoea time in patients with difficult airways. Anaesthesia. 2015;70(3).

9. Hatch LD, Grubb PH, Lea AS, Walsh WF, Markham MH, Whitney GM, et al. Endotracheal Intubation in Neonates: A Prospective Study of Adverse Safety Events in 162 Infants. Journal of Paediatrics. 2016;168.